Research has involved the study of the immunologic and genetic mechanisms involved in the development and expression of autoimmune disease. Two autoimmune strains of mice NZB and PN, have been used to study (a) phenotypic and functional abnormalities of T and B lymphocytes prior to and after the onset of disease symptoms and (b) the genetic control of these abnormalities. NZB and PN B lymphocytes undergo spontaneous polyclonal activation characterized by a decrease in the ratio of cell surface IgD/IgM, a marked increase in plasma cell frequency, an elevated rate of IgM secretion/plasma cell, and the production of autoantibodies specific for thymocytes and erythrocytes. In NZB mice, genetic studies showed that alterations in cell surface IgD expression and production of anti-erythrocyte antibodies are recessive traits, whereas plasma cell frequency, control of IgM secretion, and production of anti-thymocyte antibodies are governed by one or more dominant or semi-dominant genes. NZB and PN T cells make an unexpected primary cytotoxic T cell response to H-2-compatible cells in vitro. In NZB mice this response is controlled by two genes one of which is linked to Ly9 on chromosome 1. The genes controlling T cell dysfunction are different from those controlling polyclonal B cell activation.